Bialicyclic amino acids

ABSTRACT

THE COMPOUNDS ARE BIALICYCLIC AMINO ACIDS WHICH ARE USEFUL AS ANTI-INFLAMMATORY AGENTS IN WARMBLOODED ANIMALS. THE COMPOUNDS ARE ALSO USEFUL, WHEN THEIR AMINO GROUPS ARE PROPERLY BLOCKED, FOR REACTING WITH 6-AMINOPENICILLANIC ACID, OR DERIVATIVES THEREOF, TO PREPARE PENICILLINS HAVING ANTIBIOTIC ACTIVITY, OR AS INTERMEDIATES IN THE PREPARATION OF THEIR CORRESPONDING N-CARBOXYANHYDRIDES WHICH MAY BE REACTED DIRECTLY WITH 6-AMINOPENICILLANIC ACID, OR DERIVATIVES THEREOF, TO PREPARE SAID PENICILLINS.

United States Patent Office 3,704,312 Patented Nov. 28, 1972 3,704,312BIALICYCLIC AMINO ACIDS Peter B. Russell, Villanova, Horace FletcherIII, Pottstown, and Harvey E. Album, West Chester, Pa., assignors toAmerican Home Products Corporation, New York, N.Y. No Drawing. FiledOct. 30, 1970, Ser. No. 85,748 Int. Cl. C07c 101/04 US. Cl. 260-514 R 12Claims ABSTRACT OF THE DISCLOSURE The compounds are bialicyclic aminoacids which are useful as anti-inflammatory agents in warmbloodedanimals. The compounds are also useful, when their amino groups areproperly blocked, for reacting with 6-aminopenicillanic acid, orderivatives thereof, to prepare peni cillins having antibiotic activity,or as intermediates in the preparation of their correspondingN-carboxyanhydrides which may be reacted directly with6-aminopenicillanic acid, or derivatives thereof, to prepare saidpenicillins.

BACKGROUND OF THE INVENTION DESCRIPTION OF THE INVENTION We havediscovered a new series of Z-aminohexahydro- Z-indanecarboxylic acidswhich include those compounds encompassed within the followingstructural formula:

R (CH2)n COOH \C Qm NH2 wherein R and R are selected from the groupconsisting of hydrogen, lower alkyl, lower alkoxy, phenyl and phenoxy; nis an integer from to 1; and m is an integer from 1 to 3, with theproviso that when n is 0, m is always from 2 to 3.

Generally, the novel Z-amino acids (1) of the invention may be preparedby utilizing as starting materials, the corresponding hydantoins ofFormula II below:

wherein R R n and m again have the same meanings described with respectto Formula I above. Inv said preparation of the novel compounds ofFormula (.I), the corresponding hydantoins of Formula II are refluxed instrong base, followed by adjusting the mixture to pH 2 with concentratedhydrochloric acid, for example, and then filtering the mixture. Thefiltrate may then be adjusted to pH 6 as by addition of concentratedammonia hydroxide, at which time the aminocarboxylic acid of Formula Icrystallizes from solution.

The starting material hydantoins of Formula II may be prepared by knownprocedures for making bialicyclic hydantoins. For example, to obtain thestarting material bialicyclic hydantoins, a suitable a-hexahydroindanoneor hexahydrotetralone may be heat-reacted with ammonium carbonate andpotassium cyanide in an inert organic solvent. The reaction mixture maybe cooled, poured into water and acidified to a low acid pH withconcentrated hydrochloride acid, for example. The crude product may thenbe dissolved in diluted sodium hydroxide, filtered, and the filtratere-acidified. The final pure product may then be obtained by filteringand drying.

In an alternative mode of preparation of the compounds of Formula I, thecorresponding unsaturated amino-substituted indaneor tetralenecarboxylicacid may be hydrogenated in the presence of a suitable catalyst.

As referred to hereinbefore, the novel compounds of Formula I abovesurprisingly show anti-inflammatory activity when administered toWarm-blooded animals.

An inflammation is an abnormal condition of the tissues of some part ofthe body in which there is swelling, redness, heat and pain. It involvesthe process by which the body attempts to rid itself of bacteria,poisons, or other foreign substances which irritate or injure thetissues. The blood vessels in the affected part expand, causing moreblood to flow into the irritated or injured area. The increased amountof blood in the affected part causes the redness, and the expanded bloodvessels press on sensory nerves to cause the pain that may accompany aninflammation. In those instances where the presence of bacteria isinvolved, white blood corpuscles pass through the blood vessels into theinjured or invaded area to destroy many bacteria in situ. (Theaccumulation of bacteria and white corpulscles occurring in aninflammation is the matter termed pus.

It is well known that agents which are effective against inflammationsare active also in preventing both the clinical and histopathologicchanges which occur in experimentally induced granuloma in test animals.Such agents include the compounds prednisolone and phenylbutazone, eachof which has been shown to be active against inflammations in testanimals. Thus, experimentally induced infiammations in test animals mayserve as a test standard for anti-inflammatory activity in general.

An experimentally induced inflammation found to be valuable forcomparing the anti-inflammatory activity of a compound to be tested,with that of the aforesaid standard compound, may be caused by theinsertion of cotton pellets into bilaterally adrenalectomized testanimals in accordance with the procedure described by C. A. Winter etal. in Federation Proceedings, March-April 1963, vol. 22, No. 2, PartI., and followed in Test Method A below:

Test Method A Pursuant to the test procedure of C. A. Winter et al.referred to above, male Wistar rats, weighing grams are bilaterallyadrenalectomized. The adrenalectomized rats are anesthetized and twocotton pellets are inserted subcutaneously in each animal. The cottonpellets are preferably Johnson and Johnson Dental Rolls (1), havingweight ranges of 38:1; 40:1; 41:1; 42:1; 43:1; and 44:1 mg. The animalsare then provided with 1% saline solution containing 0.01% glucose, anda standard stock diet, and the room temperature maintained at 78-80 F.Beginning on the same day of the insertion ofthe cotton pellets,treatment is instituted by oral administration of 1.5 and 3.0 mg. ofselected test compounds in aqueous solution of carboxymethyl cellulose(0.5%) with respect to half the rats. The treatment is administeredtwice daily for five consecutive days for a total of ten doses.

All the rats (both those treated and the control group) are autopsied onthe seventh day and the granulomas (cotton pellets) are removed. Thepellets are dried for 72 hours at 80 C. and then maintained for 24 hoursat room temperature. The pellets are then weighed individually to thenearest 0.1 mg.

The anti-inflammatory activity of the test compounds may then beexpressed as percent inhibition, which is determined with the use of thefollowing formula:

. 100 X av. pellet wt. increase for treated Av. pellet wt. increase forcontrol The statistical significance and percent relative potency of thetest compound is then compared with that of the reference standard used.

It is also well known that agents which are effective againstinfiammations are active also in preventing both the clinical andhistopathologic changes which occur in experimentally-induced edema intest animals. In addition to phenylbutazone, which is also useful inTest Method A supra, other standard compounds for the edema test areaspirin, hydrocortisone, indomethacin, flufenamic and mefanarnic acid.Experimentally-induced edema valuable for comparing theanti-inflammatory activity of a compound to be tested, with that of oneof the aforesaid standard compounds, follows the procedures suggested byC. A. Winter et al. in Proc. Soc. Exp. by Biol. and Med. 111:544, 1962and by Buttle et al. in Nature 1791629, 1957, as described in TestMethod B below:

are utilized. The compound to be tested is administered orally as asolution or suspension in distilled water (plus 2 drops of Tween 80) ina volume of ml./kg. Each compound under test is given to six rats andthe vehicle alone is administered to six more rats as a control. Sixtyminutes after drug administration, edema is induced by an injection of0.05 ml. of 1 percent carrageenin in saline into the subplantar tissueof each rats right hind paw. Paw volume is then immediately measuredvolumetrically with a plethysmograph and again three hours later. Themean volume of swelling for the control group is calculated and comparedwith that of the test groups. Compounds that inhibit swelling by 23percent as compared to the controls are considered active. Inhibition iscalculated by the following formula:

Mean vol. swelling of control X100 The statistical significance of thecompounds may then be compared with that of the reference standard whichis selected from the group of compounds referred to previously.

In the use of the compounds of Formula I as antiin-flammatory agents,they may be administered alone or in combination with pharmaceuticallyacceptable carriers, and the proportion of which is determined by thesolubility and chemical nature of the compound selected, the chosenroute of administration, and standard pharmaceutical practice. Forexample, they may be administered orally in the form of tablets orcapsules, which may contain conventional excipients, or in the form ofsolutions; or they may be injected parenterally, that is,intramuscularly, intravenously or subcutaneously. For parenteraladministration, they may be used in the form of sterile solutionscontaining other solutes, for example, enough saline or glucose to makethe solutions isotonic.

v v v 4 The dosage of the present therapeutic agents will vary with theform of administration and the particular compound chosen. It willgenerally be found that when the composition is administered orally,larger quantities of the active agent will be required to produce thesame effect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afiord effective results withoutcausing any harmful or deleterious side effects.

Compounds of Formula I have shown a 40% inhibition at an oral dose of 60mg./kg. when tested in accordance with Test Method A, and a 36%inhibition at an oral dose of mg./kg. when tested in accordance withTest Method B.

The surprising eflicacy ofthe compounds of Formula I above in thetreatment of inflammations in accordance with the foregoing testprocedures has clearly indicated that they are extremely active,relatively non-toxic, longacting anti-inflammatory agents.

The following examples are illustrative of the preparation of compoundshaving the aforesaid anti-inflammatory activity, but are not to beconsidered necessarily limitative thereof:

EXAMPLE 1 EXAMPLE 2 Utilizing the procedure of Example 1 and thestarting materials given in Table I below, the correspondingantiinflarnmatory amino acids of Formula I also given in said table, areobtained:

TABLE I Final amino acid Starting amino acid 1-amino-5-butyl indanecarboxylic l-amino-fi-butyl-a-hexahydroacid. iudane carboxylic acid.1-amin0-5-butoxy-tetralene 1-amino-5-but0xy-hexahydroearboxylic acid.tetralene carboxylic acid. l-aminM-phenyl-indane earboxylicI-aminOA-phenyl-a-hemhydroacid indane earboxylic acid.

1-amino 6-methy1-hexahydrotct-ralene carboxylic acid.2-amin0-5-methyl-2-hexahydroindane-2-carboxylic acid.2-aminot-ethoxy-Z-hexahydtol-amino-trmethyl-tetralene carboxylic acid.

2-amino-5-methyl-2-indane-2- carboxylic acid.

2-amino-4-eth0xY-2-indane 2- carboxylic acid. indane-Z-carboxylic acid.2-amino-6-methoxy-tetraleue 2-amino-fi-methoxy-hexahydrocarboxylic acid.tetralene carboxylic acid. 2-amino-4-phenoxy-2-indane-22-amino-4-phenoxy-2-hexahydrocarboxylic acid. indane-Z-carboxyllc acid.

We claim:

1. An amino carboxylic acid of the formula:

R1 1 1 on 0H2)... l iwherein R is selected from the .group consisting ofhydrogen, lower alkyl, lower alkoxy, phenyl and phenyloxy; n is aninteger from 0 to 1; and m is an integer from 1 to 2, with the provisosthat when n is 0, m is always 2, and when n is 1, m is always 1.

2. An amino carboxylic acid as defined in claim 1, which is:l-aminohexahydroindanecarboxylic acid.

'3. An amino carboxylic acid as defined in claim 1, which is:2-aminohexahydroindane-2-carboxylic acid.

4. l-amino 6 methoxyhexahydrotetralenecarboxylic acid.

5. l-amino-S-butyl-a-hexahydr0indane carboxylic acid.

6. l-amino 5 butoxy-hexahydrotetralene carboxylic acid.

7. l-amino 4 phenyl-a-hexahydroindane carboxylic acid.

8. l-amino 6 phenoxy-hexahydrotetralene carboxylic acid.

9. Z-amino 5 methyl 2 hexahydroindane-2carboxylic acid.

10. 2-amino 4 ethoxy-Z-hexahydroindane-Z-carboxylic acid.

6 11. 2 amino 6 methoxy-hexahydrotetralene carboxylic acid.

12. Z-amino 4 phenoxy-2-hexahydroindane-2-carboxylic acid.

References Cited Chisolrn et al., Tet. Lett. 15, 1372 (1967).

LORRAINE A. WEINBERGER, Primary Examiner O R. GERSTL, Assistant Examiner-U.S. Cl. X.R.

